There are substantial changes in skeletal metabolism during pregnancy (for fetal skeletal mineralization), lactation (for milk production), and after weaning (to reconstitute mineral stores). Recent evidence indicates considerable reconstitution of skeletal tissues after lactation ("recovery"). The goals of the presently proposed studies are to, first, determine the mechanisms of this anabolic phase in the female, and, second, to utilize this information to develop paradigms and strategies for osteopenias (e.g., postmenopausal osteoporosis). The following Specific Aims are proposed: 1) to determine the "tissue-level" mechanisms of cancellous and cortical bone loss during lactation and skeletal recovery after lactation. It is hypothesized that tissue-level modeling and remodeling mechanisms protect skeletal structure and function. Changes at different bone compartments and envelopes will be determined using morphometric, chemical and absorptiometric methods in rats; 2) to determine the basic endocrine environment during lactation and recovery after lactation. Endocrine events will be correlated with tissue-level skeletal mechanisms; 3) to test the hypothesis that the re-establishment of an estrus cycle is important in skeletal preservation during and after lactation. It is suggested that re-establishment of the menstrual cycle is important for recovery in the human and this will be modeled with natural estrus initiation or delay (by induction of pseudopregnancy) in rats; 4) to test the hypothesis that physiologically relevant levels of transiently elevated parathyroid hormone (PTH) which occur during lactation are anabolic, rather than catabolic. Shorter-term changes in endogenous PTH will be measured and then these levels will be replicated in a known PTH-responsive model to assess anabolic actions. (The applicant suggests that this could be the first demonstration of a physiologically anabolic role of PTH.); and 5) to test the hypothesis that mechanical loading is a critical determinant of skeletal reconstitution after lactation. For this, an established model of skeletal unloading will be used. Collectively, these studies are intended to provide significant new information on perhaps one of the most anabolic phases in the life-cycle of the adult female skeleton.